ABSTRACT Despite recent advances in targeting cancer cells, chemotherapy remains a mainstay of oncology, extending survival and providing cures for many types of cancer. However, chemotherapy that ablates or suppresses bone marrow cells can be debilitating even when combined with autologous hematopoietic stem cell transplantation (HSCT). The treatment causes severe side effects such as anemia, neutropenia and thrombocytopenia, the consequences of which include hospitalization, treatment delays, and dose reductions that compromise treatment efficacy and can even result in death. Although expensive, recombinant growth factors can assist with recovery from anemia and neutropenia; however, thrombocytopenia remains an unmet medical need. Platelet transfusions provide temporary support but do not correct the underlying basis of thrombocytopenia, which results from compromised stem/progenitor function. Alterna has developed a novel technology called SHIPi that consists of the in vivo delivery of compounds that inhibit phosphatidylinositol- 3,4,5-trisphosphate 5-phosphatase 1 (SHIP1), a protein expressed in hematopoietic cells. SHIP1 negatively regulates the proliferation of stem cells, inviting the hypothesis that inhibiting SHIP1 would increase stem cell proliferation and survival. Indeed, investigations of SHIPi have demonstrated that the technology can increase neutrophil numbers and also abrogate the growth of certain hematologic cancers. More recently, SHIPi was found to promote expansions of hematopoietic stem cells and mesenchymal stem cell compartments. It can also super-induce the production of endogenous granulocyte-colony stimulating factor (G-CSF) that acts on the hematopoietic stem/progenitor cell (HS/PC) compartment. Moreover, SHIPi accelerates hematologic recovery after myelosuppressive radiation treatment, including the recovery neutrophils and platelets. These inherent properties of SHIPi provide a mechanistic advantage over recombinant growth factors like G-CSF and erythropoietin in promoting blood cell recovery. The objective of this Phase I research project is to test and develop SHIPi approaches that will lead to improved hematologic recovery following chemotherapy (myelo- suppressive or -ablative) combined with HSCT. Specifically, after synthesizing sufficient amounts of two highly-active SHIP1 inhibitors, the compounds (K103, K161) will be characterized in vivo dose-escalation and pharmacokinetic studies in rats to ensure that there will be appropriate exposure to the compounds in subsequent animal studies. Next, the compounds will be tested, in vitro, for off-target effects. And the final line of investigation will use a murine model of chemotherapy-induced myelosupression to determine if the administration of SHIP1 inhibitors after chemotherapy enhances blood cell recovery. Mice that receive chemotherapy and are treated using SHIPi are expected to show more rapid recovery of blood cell components compared to untreated (negative) and G-CSF-treated (positive) controls.